1. Field of the Invention
The invention relates to a method to control the adrenal secretion of glucocorticoids in male livestock without impairing the animal's immune response.
2. Description of the Prior Art
Bovine respiratory disease complex (shipping fever) has long been recognized as a multifactorial condition of calves and adult cows involving the combination or management, stress, viral, and bacterial factors [Hoerlein et al., J. Am. Vet. Med. Assoc., 131: 123-127, (1957); Roth, "Immunosuppression and Immunomodulation in Bovine Respiratory Disease", In: R. W. Loan (ed.), Proceedings of the North American Symposium on Bovine Respiratory Disease, Texas A&M University Press, College Station, (1983), pages 143-192; and Filion et al., Can. J. Comp. Med., 48: 268-274, (1984)]. Calves are rendered susceptible to the disease complex as a result of suppression of the animal's immune system. The organism responsible for the acute fibrinous pneumonia associated with this disease complex is usually Pasteurella hemolytica, which is a normal resident of the nasal microflora. In stressed calves this microorganism can proliferate and subsequently colonize in the lower respiratory tract.
Major factors which account for the immunosuppression are viral and/or stress related. Elevated levels of glucocorticoids and especially cortisol resulting from stress have been found to suppress several aspects of the immune system in cattle [Roth, "Cortisol as Mediator of Stress-Associated Immunosuppression in Cattle", In: G. Moberg (ed.), Animal Stress, Waverly Press, Baltimore, (1985), pages 225-243] and other animals.
Progesterone has been shown to have antiglucocorticoid activity in vitro in rats and mice [Naylor et al., Endocrinol. 107: 117-121 (1980) and J. Steroid Biochem. 14: 1303-1309 (1981); Grunfeld et al., Hypertension 7: 292-299 (1985); and Stevenson et al., Int. J. Immunopharmac. 10: 1-6 (1988)]. In cattle, Capuco et al. [Proc. Soc. Exp. Biol. Med. 164: 386-393 (1980)] have demonstrated that progesterone could block binding of the synthetic glucocorticoid, dexamethasone, to the glucocorticoid receptor in mammary tissue. Synthetic progestins including 6-.beta.-bromoprogesterone [Naylor (1980), ibid.] and RU 486 [Bertagne et al., J. Clin. Endocrinol. 59: 25-28 (1984)] have also been found to have antiglucocorticoid activity in the rat and human, respectively. Other, 6-methylated progestins have been shown to possess adrenal depressant activity [Elton et al., Proc. Soc. Expt. Biol. Med. 103: 175-177 (1960)], while Middleton et al. [Can. J. Vet. Res. 51: 60-65 (1987)] found that megesterol acetate reduced cortisol secretion in cats. May et al. [Life Sci. 46: 1627-1631 (1990)] showed that dehydroandrosterone (DHEA) administration could antagonize the effect of glucocorticoids and would prevent thymic involution normally induced by glucocorticoids.
A commonly used synthetic progesterin which is used extensively in female cattle to suppress estrus is melengesterol acetate (MGA), fed at a rate of 0.25 to 0.50 mg/head/day. Administration of very high pharmacological levels of the compound has demonstrated adrenal corticoid-like activity, with inhibition of the inflammatory response in rats [Duncan et al., Fertil, Steril. 15: 419-432 (1964)]. McKinney et al. [Toxicol. Appl. Pharm. 7:491 (1951)] found that MGA reduced glucocorticoid levels in stressed female rats fed very high doses of the compound. However, upon oral administration of lower doses to dairy heifers, MGA did not exhibit any effect on total corticoid levels [Randel et al., J. Animal Sci. 35: 389-397 (1972)]. In later work, Upadhyay et al., showed that feeding MGA to poultry did not affect body weight gains [Indian J. Anim. Res. 18: 94-98 (1984)].